International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E27 Mapping and Positional Cloning of TNF-Response Modifier Genes in the Mouse

Ben Wielockx1, Jan Staelens1, Rosemary Elliott2 and Claude Libert1. 1VIB/RUG Department Molecular Biology, Mouse Molecular Genetics Group, Ghent, Belgium; 2Roswell Park Cancer Institute, Buffalo, NY

Tumor Necrosis Factor (TNF) is a cytokine with very interesting antitumor activities, especially when applied in combination with Interferon. Unfortunately, TNF is also a mediator of the Systemic Inflammatory Response Syndrome (SIRS) so that injection of TNF in cancer patients and experimental animals causes shock-like phenomena, characterized by drop in blood pressure, hepatotoxicity and bowel necrosis. We are especially interested in identifying, cloning and eventually applying endogenous factors that can counteract the lethal effects of TNF. We observed that, compared to C57BL/6J and BALB/cJ, DBA/2J mice are significantly resistant towards an intravenous injection of TNF. Using the complete set of 26 BXD recombinant inbred strains and a dose of TNF lethal for C57BL/6J mice but not for DBA/2J, we found close linkage with the SERPIN locus on distal chromosome 12. QTL analysis of lethality, drop in body temperature and induction of another cytokine, Interleukin-6, confirmed the importance of this TNF protection (TNFp) locus (Libert et al., 1999). Furthermore, we have reduced the critical region on chromosome 12 to about 0.5 cM by mapping microsatellite markers using the BXD mapping panel and we have built a BAC contig of the critical region, which will be used to select DBA/2 derived candidate genes by hybridisation. Backcross and intercross experiments starting from C57BL/6J and DBA/2CRL (even more resistant to TNF than DBA/2J) are underway to identify other loci that could influence TNF-induced lethal SIRS.

CL is a senior research associate with the VIB and BW holds an IWT fellowship.

Reference:

Libert, C., B. Wielockx, G.L. Hammond, P. Brouckaert, W. Fiers and R.W. Elliott, 1999, Identification of a locus on distal mouse chromosome 12 that controls resistance to tumor necrosis factor-induced lethal shock, Genomics, 55(3):284-9.

 


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